Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

The aims of our study were to assess variation in intensity of treatment in children with K-ATP CHI over time, and to review outcomes of medically treated K-ATP CHI patients in follow up assessments.

A cohort of patients with K-ATP CHI (mutations in ABCC8/KCNJ11) treated by medical therapy (n = 21) was identified from a group of patients (n = 404) in a specialist centre for CHI between April 2006 and July 2016, with local Research Ethics approval. Genetic investigations were performed in 269 patients only within the cohort. In the remainder, genetic investigations were not performed because CHI resolved in early infancy or patients remained on low dose diazoxide. In those undergoing genetic testing, 71 patients had mutations in ABCC8/KCNJ11, 10 patients had mutations in other genes related to CHI (HNF4A, GCK, HADH, GLUD1) and 10 patients had variants of uncertain clinical significance. Within the group of 71 patients with ABCC8/KCNJ11 mutations, 39 patients underwent pancreatic surgical treatment (subtotal pancreatectomy or focal lesionectomy); patients who were not surgically treated, i.e. medically treated (n = 21) were recruited to the study. Eleven patients who were also medically treated were not recruited because they either presented between January 2016 and July 2016, or insufficient clinical information was available in follow up.

The diagnosis of CHI was made in patients presenting to this centre using well-established criteria [1, 2]. Patients underwent rapid K-ATP channel gene mutation analysis as per protocol, as previously reported [10]. Variants either previously reported or considered likely to be pathogenic were included in the cohort. One variant reported as pathogenic in our patient but classified elsewhere as being a variant of uncertain significance was also included.

The diagnosis of focal CHI was made on the basis of a paternal heterozygous mutation in ABCC8/KCNJ11 and confirmed by identification of a solitary lesion in the pancreas during 18-fluoro-dopa PET-CT scanning [2]. Those with no clear foci were diagnosed as diffuse CHI. Diffuse CHI was also presumed if the patient had maternal heterozygous, homozygous, or compound heterozygous mutations in ABCC8/KCNJ11, for which 18-fluoro-dopa PET-CT scans were not performed. Patients with ABCC8/KCNJ11 mutations who required either lesionectomy for focal CHI or subtotal pancreatectomy for diffuse CHI were excluded from the cohort. Patients who underwent pancreatic biopsy or minimal resection while continuing medical therapy were included in the cohort.

Treatment variations were made on clinical grounds and individualised to patient need. Oral diazoxide was used as first line treatment, while somatostatin agonists (SSRA, octreotide, somatuline) were used as second line treatment. Carbohydrate supplements to increase energy content of milk and polyunsaturated fatty acids (PUFA) used in the management of diazoxide responsive CHI were considered as food supplements and did not preclude inclusion to the cohort [16]. The dose of Eicosapentaenoic acid (EPA) component of omega-3 fatty acid was allowed in a range of 240–480 mg per day. Responsiveness to diazoxide as treatment for CHI was determined by noting satisfactory glucose profiling and fasting tolerance as described previously [16]. Responsiveness to SSRA was also determined in a similar manner.

Children had resolution of CHI if treatment was minimised and withdrawn completely with maintenance of satisfactory glucose profiles (95% values >3.5 mmol/L) on home glucose monitoring or subcutaneous continuous glucose monitoring (CGM) [10, 16]. To achieve resolution of CHI, satisfactory fasting tolerance was mandatory with end of fast blood glucose >3.0 mmol/L, suppressed insulin concentrations and blood ketones >1.0 mmol/L measured by point of care testing and/or laboratory analysis of 3 hydroxybutyrate. Follow-up consisted of telephone reviews every 2 weeks for the first 4 months, followed by clinic reviews at 4 monthly intervals by a multi-disciplinary team including a clinician, two specialist nurse practitioners, two dietitians, a speech and language therapist and a clinical psychologist. At each review, glucose profile was assessed and medication adjusted accordingly. Children who demonstrated resolution of CHI were reviewed in clinic appointments every 6 months by a clinician and specialist nurse practitioner without wider multi-disciplinary team input. Annual home blood glucose profiles were assessed to determine glycaemic status and to ensure continuing euglycaemia. Oral glucose tolerance testing was not performed routinely in all children undergoing spontaneous resolution, in the absence of information regarding long-term utility and difficulty in administering the test in young children. Instead, home blood glucose profiling was assessed and correlated with symptoms of hypoglycaemia and hyperglycaemia. Pancreatic biopsy was not routinely undertaken in patients enrolled in the cohort. However, for patients in whom a pancreatic biopsy was undertaken as a partial resection, the tissue was analysed for characteristics of focal and diffuse CHI [17].

In addition to glycaemic outcomes in follow up assessment, the Vineland Adaptive Behavior Scales, version II (VABS-II), a questionnaire completed by parents was used to assess adaptive functioning in the domains of communication, daily living skills, social skills and motor skills after age 1.5 years (http://​www.​pearsonclinical.​com/​). Information was also obtained on the prevalence of seizures and delayed development in clinical assessment [3]. Auxology parameters were reviewed at the 2 year follow up assessment and measurements were converted to Standard Deviation Scores (SDS) [18]. Statistical analysis was performed by IBM-SPSS version 23.0 (IBM incorporated, New York, USA); Mann–Whitney test was performed to test differences between non-parametric independent variables while paired t-tests were used to test difference between paired samples.